The health of pregnant women and their unborn children is jeopardized by malarial infection in many regions of the world. When pregnant women contract malaria, maternal anemia, preterm labor, and low birth weight babies, or, in severe cases found in low endemic or epidemic situations, maternal death, abortion, and stillbirth, commonly occur. While a role for pro-inflammatory cytokine responses in malarial pathogenesis has been suggested, few mechanistic studies have explored this possibility in pregnancy. To address this important problem, we have developed a murine model for malaria during pregnancy that is characterized by mid-gestational fetal loss, similar to the outcomes seen in human severe malaria during pregnancy. The objective of this application is to characterize the immunopathogenic mechanisms that mediate malaria- induced pregnancy loss. The central hypothesis proposes thatTh1/pro-inflammatory cytokines produced during blood-stage malaria play a pivotal role in the compromise of pregnancy. The specific aims of the project are to identify the soluble immunopathogenic effectors and the relative role of anemia in fetal loss in malaria-infected mice, characterize the roles of fetal cells in this process, and characterize the molecular basis of placental pathology in malaria-infected mice. These aims will be achieved by assessing pregnancy outcome in mice with known tendencies toward Th1/pro-inflammatory and Th2/anti-inflammatory cytokine production during Plasmodium chabaudi AS infection, and by utilizing mice with null mutations in factors that manipulate the host cytokine response and mediate immunopathogenesis. Genetic manipulation of anemia will be used to assess the relatives roles of malarial anemia and cytokines in mediating fetal loss. The ability of fetal trophoblast cells to respond to the malarial infection and manipulate the placental immune environment and induce pathology will also be examined. Finally, the role of abnormal coagulation and/or fibrinolysis in inducing placental damage and fetal loss, and the dependence of these abnormalities on cytokine production patterns, will be analyzed. These studies will ultimately contribute to the development of interventions and vaccines to reduce the morbidity and mortality associated with malaria during pregnancy. Also, this work is expected to advance the field of reproductive immunology by providing insight into the complexities of the fetal/maternal relationship and the impact of infectious diseases on this relationship.